Acyclic nucleoside phosphonates as possible chemotherapeutics against Trypanosoma brucei.

Acyclic nucleoside phosphonates as possible chemotherapeutics against Trypanosoma brucei. Drug Discov Today. 2020 Mar 02;: Authors: Terán D Abstract Human African trypanosomiasis is a life-threatening illness caused by Trypanosoma brucei. Owing to the toxic side effects of the available therapeutics, new medications for this disease are needed. One potential drug target is the 6-oxopurine phosphoribosyltransferases (PRTs), the activity of which is crucial to produce purine nucleotide monophosphates required for DNA and RNA synthesis. Inhibitors of the 6-oxopurine PRTs that show promising results as drug leads are the acyclic nucleoside phosphonates (ANPs). ANPs are very flexible in their structure, enabling important conformational changes to facilitate the binding of this class of compounds in the active site of the 6-oxopurine PRTs. PMID: 32135205 [PubMed - as supplied by publisher]
Source: Drug Discovery Today - Category: Drugs & Pharmacology Authors: Tags: Drug Discov Today Source Type: research

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(Johannes Gutenberg Universitaet Mainz) Professor Ute Hellmich of Johannes Gutenberg University Mainz (JGU) has launched a new research project investigating essential membrane proteins of parasites, some of which can cause a neglected tropical disease (NTD) such as African sleeping sickness and Chagas disease.
Source: EurekAlert! - Infectious and Emerging Diseases - Category: Infectious Diseases Source Type: news
The protozoan parasite Trypanosoma brucei is the etiological agent of human African trypanosomiasis (HAT). HAT, together with other neglected tropical diseases, causes serious health and economic issues, especially in tropical and subtropical areas. The classical antifolates targeting dihydrofolate reductase (DHFR) are ineffective towards trypanosomatid parasites owing to a metabolic bypass by the expression of pteridine reductase 1 (PTR1). The combined inhibition of PTR1 and DHFR activities in Trypanosoma parasites represents a promising strategy for the development of new effective treatments for HAT. To date, only monoc...
Source: Acta Crystallographica Section D - Category: Biochemistry Authors: Tags: Trypanosoma brucei pteridine reductase 1 antiparasitic drugs high-resolution crystal structure tricyclic compound human African trypanosomiasis research papers Source Type: research
We report here the identification spiro-containing derivatives as inhibitors of TR fromTrypanosoma brucei (TbTR), the parasite responsible for Human African Trypanosomiasis. The hit series, identified by high throughput screening, was shown to bindTbTR reversibly and to compete with the trypanothione (TS2) substrate. The prototype compound 1 from this series was also found to impede the growth ofTrypanosoma brucei parasitesin vitro. The X-ray crystal structure ofTbTR in complex with compound 1 solved at 1.98 Å allowed the identification of the hydrophobic pocket where the inhibitor binds, placed close to the catalyti...
Source: PLoS Neglected Tropical Diseases - Category: Tropical Medicine Authors: Source Type: research
Conclusions/SignificanceThe 2020 goal of HAT elimination as a public health problem is within grasp, and eligible countries are encouraged to request validation of their elimination status. Beyond 2020, the HAT community must gear up for the elimination of gambiense HAT transmission (2030 goal), by preparing for both the expected challenges (e.g. funding, coordination, integration of HAT control into regular health systems, development of more adapted tools, cryptic trypanosome reservoirs, etc.) and the unexpected ones.
Source: PLoS Neglected Tropical Diseases - Category: Tropical Medicine Authors: Source Type: research
ConclusionsThe high correlation between extinction probability and daily female adult mortality gives a strong argument that control techniques which increase daily female adult mortality may be the single most effective means of ensuring eradication of tsetse population.
Source: PLoS Neglected Tropical Diseases - Category: Tropical Medicine Authors: Source Type: research
Abstract Pactamycin and jogyamycin are aminocyclopentitol natural products, where each core carbon bears a stereodefined alcohol or amine moiety. Their structural complexity, coupled with the diversity of functional groups co-existing in a condensed space, make them fascinating synthetic targets in their own right. Pactamycin and its derivatives bind to the 30S ribosomal subunit and display activity against parasites responsible for drug-resistant malaria and African sleeping sickness; however, efforts to develop their therapeutic potential have been hampered by their cellular toxicity. Interestingly, bioengineere...
Source: Angewandte Chemie - Category: Chemistry Authors: Tags: Angew Chem Int Ed Engl Source Type: research
Animal African trypanosomiasis (AAT) is a life-threatening vector-borne disease, caused by trypanosome parasites, which are principally transmitted by tsetse flies. In Kenya, the prevalence of drug-resistant t...
Source: BMC Research Notes - Category: Research Authors: Tags: Research note Source Type: research
ari R Abstract In this paper, starting from the reversible rhodesain inhibitors 1a-c endowed with K i values in the low micromolar range towards the target protease, we now designed a new series of peptidomimetics 2a-g containing the benzodiazepine scaffold as a β -turn mimetic, and characterized by a specific peptide sequence for the inhibition of rhodesain. Considering that an irreversible inhibition is strongly desirable in the case of a parasitic target, a vinyl ester moiety acting as Michael-acceptor has been introduced as the warhead; finally, this portion has been functionalized in order to evaluate th...
Source: ChemMedChem - Category: Chemistry Authors: Tags: ChemMedChem Source Type: research
Abstract Trypanosomatids are unicellular parasitic protozoa. Many of the species of this genera cause severe diseases in human, such as Leishmaniasis, African trypanosomiasis and Chagas disease. These parasites possess a single reticular mitochondrion with a concatenated structure of mitochondrial DNA known as kinetoplast or kDNA. kDNA encodes few essential mitochondrial proteins but no tRNAs. Therefore, trypanosomatid mitochondrion import a full set of nucleus-encoded tRNAs for mitochondrial translation. Recent advances indicated that mitochondrial protein translocases, particularly the subunits of the ATOM compl...
Source: Gene - Category: Genetics & Stem Cells Authors: Tags: Gene Source Type: research
Abstract The Trypanosomatid family are a diverse and widespread group of protozoan parasites that belong to the higher order class Kinetoplastida. Containing predominantly monoxenous species (i.e. those having only a single host) that are confined to invertebrate hosts, this class is primarily known for its pathogenic dixenous species (i.e. those that have two hosts), serving as the aetiological agents of the important neglected tropical diseases (NTDs) including leishmaniasis, American trypanosomiasis (Chagas disease) and human African trypanosomiasis. Over the past few decades, a multitude of studies have invest...
Source: International Journal for Parasitology - Category: Parasitology Authors: Tags: Int J Parasitol Source Type: research
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